Prevention of lymphocele or seroma after mastectomy and axillary lymphadenectomy for breast cancer: systematic review and meta-analysis

Seroma or lymphocele remains the most common complication after mastectomy and lymphadenectomy for breast cancer. Many different techniques are available to prevent this complication: wound drainage, reduction of the dead space by flap fixation, use of various types of energy, external compression dressings, shoulder immobilization or physical activity, as well as numerous drugs and glues. We searched MEDLINE, clinicaltrials.gov, Cochrane Library, and Web of Science databases for publications addressing the issue of prevention of lymphocele or seroma after mastectomy and axillary lymphadenectomy. Quality was assessed using Hawker’s quality assessment tool. Incidence of seroma or lymphocele were collected. Fifteen randomized controlled trials including a total of 1766 patients undergoing radical mastectomy and axillary lymphadenectomy for breast cancer were retrieved. The incidence of lymphocele or seroma in the study population was 24.2% (411/1698): 25.2% (232/920) in the test groups and 23.0% (179/778) in the control groups. Neither modification of surgical technique (RR 0.86; 95% CI [0.72, 1.03]) nor application of a medical treatment (RR 0.96; 95% CI [0.72, 1.29]) was effective in preventing lymphocele. On the contrary, decreasing the drainage time increased the risk of lymphocele (RR 1.88; 95% CI [1.43, 2.48). There was no publication bias but the studies were of medium to low quality. To conclude, despite the heterogeneity of study designs, drainage appears to be the most effective technique, although the overall quality of the data is low.

www.nature.com/scientificreports/ Two previous Cochrane meta-analyses have evaluated fibrin glues and wound drainage and concluded on the inefficacy of fibrin glues and moderate efficiency of drainage supported by low quality studies 3,8 . To our knowledge, no meta-analysis has compared all proposed techniques for seroma prevention after mastectomy and axillary lymphadenectomy.

Materials and methods
This meta-analysis was performed in accordance with the 2009 Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines and the Cochrane Collaboration recommendations 12 . The "Prevention of seroma after breast cancer surgery" trial was registered on the Open Science Framework (OSF) platform https:// doi. org/ 10. 17605/ OSF. IO/ RFVG6. Literature search. We searched MEDLINE, clinicaltrials.gov, Cochrane Library, and Web of Science databases for publications of randomized controlled trials (RCT) and clinical trials addressing the issue of prevention of lymphocele or seroma after mastectomy and axillary lymphadenectomy. Various combinations of the following terms were searched: "lymphocele", "lymphorrhea", "seroma", "breast cancer", "breast surgery". Eligibility criteria. Three authors independently conducted the initial research to evaluate eligibility criteria (AC, MLB, KM). We selected randomized controlled trials and clinical trials published after January 2000 in English, including more than 50 participants, reporting the incidence of lymphocele or seroma after mastectomy and axillary lymphadenectomy for breast cancer. The latest search was performed in March 2021.
The following publications were excluded: retrospective studies, case reports, letters to the editor, publications concerning plastic surgery, brachytherapy or radiation therapy.
Data collection process and outcome measures. Three authors independently performed data collection using a standardized data extraction table (AC, MLB, KM). The following data were extracted: author, year and country of publication, study characteristics, prevention technique, inclusion and exclusion criteria, number of patients, data necessary to build 2 × 2 contingency tables.

Statistical analysis. Publication bias.
A funnel plot was used to visualize publication bias. The estimate of the difference between groups was pooled, depending upon the effect weights of the variance estimate determined in each trial. Egger's test was used to assed asymmetry of the funnel plot 13 .
Outcomes. For dichotomous outcomes, the Mantel-Haenszel method was used for calculation of relative risk (RR) under the fixed-effect and random-effects models 13 . The Forest plot was used for graphic display of the results of the meta-analysis. The heterogeneity of studies was calculated using the I 2 index. The I 2 value was interpreted by balancing the direction and magnitude of I 2 with its statistical significance, using the values in the Cochrane Handbook for Systematic Reviews of Interventions as a guide 14 : 0% to 40%: might not be important; 30% to 60%: may represent moderate heterogeneity; 50% to 90%: may represent substantial heterogeneity; 75% to 100%: represents considerable heterogeneity. Meta-analyses with insignificant heterogeneity were calculated using the fixed-effects model 15 . For meta-analyses with low or moderate heterogeneity, the random-effects model was used 16 . The square around the estimate represents the accuracy of the estimation (sample size) and the horizontal line represents the 95% confidence interval (95% CI).
Data were entered in an Excel file and all statistical analyses were performed using Rstudio software (RStudio, PBC, Boston, USA). A P value < 0.05 was considered to be statistically significant.
Quality assessment of the studies included. We used a quality assessment tool elaborated by Hawker et al. 17 in 2002 for systematic review of qualitative evidence. The scale contains nine items assessing abstract/title, introduction/aims, method/data, sampling, data analysis, ethics/bias, results, transferability and implications. Each item is rated as "good", "fair", "poor" and "very poor". Lorenc et al. 18 added a graduation to this scale by assigning answers from 1 point (very poor) to 4 points (good), to provide a final score for each study (9 to 36 points). The overall quality grades were defined by the following description: grade A (high quality) 30-36 points; grade B (medium quality), 24-29 points and grade C (low quality), 9-24 points. Each of the three readers assessed the studies independently. When differences were observed, a majority agreement was reached.

Results
Study selection. The PRISMA flow diagram explaining the literature search strategy and trial selection is presented in Fig. 1. Fifteen randomized controlled trials including a total of 1766 patients undergoing mastectomy and axillary lymphadenectomy for breast cancer were retrieved from the electronic databases. Analysis was based on 920 patients in the test groups and 878 patients in control groups. The characteristics of the trials included in this meta-analysis are provided in Table 1. The technique used in each article is described in Table 1. The incidence of lymphocele or seroma in the study population was 24.9% (411/1648): 29.5% (271/920) in the test groups and 23.9% (210/878) in the control groups.
As the study by Dalberg et al. 22 compared two different techniques in two separate groups of patients, we decided to divide this study into one group treated by drainage and the other group treated by the fascia preservation surgical technique. Publication bias. The funnel plot did not show any asymmetry (Supplemental Fig. 1). Egger's test did not reveal any publication bias (p = 0.36).
Prevention of seroma regardless of the technique. Significant       www.nature.com/scientificreports/ One study that investigated prevention of lymphocele or seroma using physical activity and manual lymphatic drainage 29 found these technique to be statistically ineffective (RR 1.67; 95% CI [0.44; 6.29]). Study quality. The results of the quality assessment are described in Supplemental Table 1. One study was considered to present high quality (Grade A), 8 studies were considered to present medium quality (Grade B), and 6 studies were considered to present low quality (Grade C).

Discussion
This work represents the first meta-analysis of all techniques proposed for the prevention of lymphocele formation after mastectomy and axillary lymphadenectomy in prospective randomized controlled trials and clinical trials. Global analysis of all of the various techniques showed that they were not effective to prevent lymphocele formation (RR 1. 23 1.29]). The overall quality of these items was moderate with 8 items presenting average quality, 6 items presenting low quality, and only one item presenting high quality.
In this study, we chose to restrict our analysis to the population at high risk of lymphocele or seroma 34 . In our meta-analysis, regardless of the definitions and techniques used to prevent seroma or lymphocele, the overall incidence of these complications was 24.2% (411/1698): 25.2% (232/920) in the test groups and 23.0% (179/778) in the control groups. The reported seroma or lymphocele incidence is dependent on the author's definition of seroma or lymphocele and the method of detection used. Risk factors for seroma formation include age, body mass index (BMI), tumor size, use of neoadjuvant chemotherapy, type of surgery (MRM versus breast-conserving surgery) 34 , axillary lymph node status, axillary lymph nodes sampled or removed, and subsequently the extent of surgical dead space produced 35 . In our meta-analysis, only one article 21 considered neoadjuvant chemotherapy to be an exclusion criterion, while most of other studies did not mention neoadjuvant chemotherapy. Other risk factors, except for the type of surgery, were not well documented. This lack of information on risk factors may result in an incidence bias.
The various techniques tested to reduce seroma or lymphocele after breast surgery are based on the different physiological theories. Six studies tested a drug for prevention of seromas. These drugs inhibit the inflammatory or immunopathological response, which is considered to play a role in seroma formation 35 . Four studies evaluated a specific surgical procedure. A French multicenter, superiority, randomized controlled trial, compared seroma formation using quilting suture versus conventional closure with drainage in 320 patients undergoing mastectomy 36 , results have not yet been published. A meta-analysis by Sajid et al. studied application of fibrin glue under skin flaps to prevent seroma-related morbidity following breast and axillary surgery 8 , but this technique failed to reduce the incidence of postoperative seroma (RR 1.02; 95% CI 0.90-1.16, p value = 0.73).
Four studies included in our meta-analysis evaluated modification of the drainage technique. Since 1947 and the first description of drainage after axillary dissection for breast cancer by Murphey 37 , drainage is the technique most commonly used to prevent lymphocele or seroma after radical mastectomy and axillary lymphadenectomy. In 2013, a Cochrane meta-analysis by Thomson et al. 3 compared wound drainage versus no wound drainage after axillary lymphadenectomy for breast carcinoma. Seven RCTs including 960 participants were identified. The quality of trials was generally low, with several studies at risk of selection bias, and no studies used blinding during treatment or outcome assessment. There was a high level of statistical variation between studies, which therefore reduces the reliability of the evidence. The R for seroma formation was 0.46 ([95% CI 0.23-0.91], p = 0.03) in favor of a reduced incidence of seroma in participants with drains inserted.
Finally, wound drainage appears to be the most effective way to prevent seroma, although no consensus has been reached concerning the optimal duration of drainage. However, persistence of foreign devices under the skin could predispose to surgical site infection. Surgical site infection is one of the possible complications after breast cancer surgery, causing significant morbidity, additional costs and which can delay initiation of adjuvant therapy. In Reiffel's review 38 of the potential association between closed-suction drains and surgical site infection, few studies suggested an increased risk of surgical site infection associated with drain placement and no studies attributed a decreased incidence of surgical site infection (including organ/space surgical site infection) with drain placement.

Conclusions
The lack of consensus concerning the definition of lymphocele or seroma is probably responsible for the heterogeneity of seroma incidence reported in the literature and the inefficacy of the techniques proposed for seroma prevention after breast cancer surgery. However, drainage is the most effective technique currently available. Yet, most studies included in the meta-analysis were evaluated to be of medium or low quality.

Data availability
The datasets used and/or analysed during the current study available from the corresponding author on reasonable request.